2.1. Expression of Major Histocompatibility Complex Antigens and Relationship to Immune Response
Surface-expressed proteins of the major histocompatibility complex (MHC) are integral for the initiation and effector functions of immune responses. Initiation of immune functions by CD4+ T cells (helpers) appears to require class II MHC antigen presentation, while cytotoxic effector functions by CD8+ T cells (cytotoxic T lymphocytes or CTLs) appear to require class I MHC antigen presentation. It is known that cell surface expression of MHC proteins correlates with human autoimmune and alloimmune diseases (reviewed in Feldman et al., in Interferon 9: 75-90, Academic Press 1987). Tissue cells in the majority of human autoimmune diseases including, for example, thyroiditis, diabetes, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, vasculitis, biliary cirrhosis and immunologically-related skin disorders, as well as alloimmune diseases such as graft vs. host disease, express abnormally elevated levels of class I and class II MHC antigens. When cells that ordinarily do not express class II antigens (e.g., fibroblasts and endothelial cells) begin to express this class of antigen, they become immunoreactive targets for lysis and destruction by CTLs (Pober et al., 1983, Nature 305: 726).
MHC antigen expression on many cell types is largely under the regulatory control of various cytokines. Cells such as macrophages, dermal fibroblasts, keratinocytes, thyrocytes, astrocytes, B islet cells, smooth muscle cells, T lymphocytes, endothelial cells and many cancer cells, require induction by cytokines for class II MHC antigen expression (Revel and Schattner, in Autoimmunity and Autoimmune Disease 223-233, Wiley 1987). Members of the interferon family are primarily involved with the upregulation of MHC expression and all types of interferons appear to enhance class I expression, although IFN-.gamma. is the best studied and most potent in this regard. In addition, the cytotoxins known as tumor necrosis factors (TNF-.alpha. and TNF-.beta.) have demonstrated the ability to enhance class I expression in fibroblasts via induction of IFN-.beta.2 (May et al., 1987, Proc. Natl. Acad Sci. USA 83: 8957). While the induction of class II antigens by IFN-.alpha. and IFN-.beta. is usually not significant, IFN-.gamma. is a potent inducer of class II molecules at the gene level (Collins et al., 1984, Proc. Natl. Acad. Sci. USA 81: 4917). Some cytokines appear to synergize with IFN-.gamma. in the induction of MHC antigen expression; for example, TNF-.alpha. and TNF-.beta. act synergistically with IFN-.gamma. on expression of class I antigens on endothelial cells without affecting IFN-.gamma.-mediated induction of class II antigens (Lapierre et al., 1988, J. Exp. Med. 167: 794).
The level of MHC antigen expression on a cell's surface is a determinant of its antigen-presenting capacity (Matis et al., 1983, Proc. Natl. Acad. Sci. USA 80: 6090). Therefore, compounds that interfere with or antagonize over-expression of MHC antigens beyond immunologically-tolerated thresholds may have therapeutic utility in, for example, slowing or stopping the progression of autoimmune diseases. In the case of transplanted organs, the expression level of the donor MHC antigens is an important determinant of the severity of the rejection response (Ferry et al., 1987, Transplantation 44: 499). Transforming Growth Factor-.beta. (TGF-.beta.) has been shown to inhibit the level of class II expression induced by IFN-.gamma. on human melanoma cells and peripheral blood mononuclear cells without affecting class I expression (Czarniecki et al., 1988, J. Immunol. 140: 4217).